MDedge Dermatology

Cosmeceutical alternatives to hydroquinone, which is now restricted in the United States from inclusion in over-the-counter (OTC) products, are proliferating, along with new strategies to improve their efficacy, according to a report at the Skin of Color Update 2021.

“Ten or 15 years ago, I was showing a slide with five [alternatives to hydroquinone]. Now there are dozens,” reported Heather Woolery-Lloyd, MD, director of the skin of color division in the department of dermatology at the University of Miami.

The growth in alternatives to hydroquinone is timely. After threats to do so for more than a decade, the Food and Drug Administration finally banned hydroquinone from OTC products in 2020. The ban was folded into the Coronavirus Aid, Relief, and Economic Security (CARES) Act passed in March of 2020 and then implemented the following September.

Until the ban of hydroquinone, OTC products with this compound were widely sought by many individuals with darker skin tones to self-treat melasma and other forms of hyperpigmentation, according to Dr. Woolery-Lloyd. Hydroquinone is still available in prescription products, but she is often asked for OTC alternatives, and she says the list is long and getting longer.
 

Niacinamide

Detailing the products she has been recommending most frequently as substitutes, Dr. Woolery-Lloyd reported that several are supported by high quality studies. One example is niacinamide.

Of the several controlled studies she cited, one double-blind randomized trial found niacinamide to be equivalent to hydroquinone for melasma on the basis of colorimetric measures. The study compared 4% niacinamide cream applied on one side of the face with 4% hydroquinone cream applied on the other side in 27 patients with melasma. Although the proportion of responses rated good or excellent on a subjective basis was lower with niacinamide (44% vs. 55%), the difference was not statistically significant and niacinamide cream was clearly active, producing objective improvements in mast cell infiltrate and solar elastosis in melasma skin as well. Both were well tolerated.

In other studies, niacinamide has been shown to be effective in the treatment of melasma when combined with other active agents such as tranexamic acid, said Dr. Woolery-Lloyd, who added that OTC products containing niacinamide are now “among my favorites” when directing patients to cosmeceuticals for hyperpigmentation.
 

Topical vitamin C

Topical vitamin C or ascorbic acid is another. Like niacinamide, topical vitamin C has also been compared with hydroquinone in a double-blind, randomized trial. Although the niacinamide trial and this study were performed 10 or more years ago, these data have new relevance with the ban of OTC hydroquinone.

In the study, 5% ascorbic acid cream on one side of the face was compared with 4% hydroquinone cream, applied on the other side, in 16 women with melasma. Again, there were no statistical differences in colorimetric measures, but good to excellent results were reported for 93% of the sides of the face treated with hydroquinone versus 62.5% of the sides treated with vitamin C (P < .05). “Hydroquinone performed better, but the vitamin C was active and very well tolerated,” Dr. Woolery-Lloyd said.

However, the ascorbic acid cream was better tolerated, with a far lower rate of adverse events (6.2% vs. 68.7%), an advantage that makes it easy to recommend to patients, said Dr. Woolery-Lloyd, who now uses it frequently in her own practice.

Liquiritin, a licorice extract, is another lightening agent increasingly included in OTC products that she also recommends. In two older studies in medical journals published in Pakistan, both the 2% and 4% strengths of liquiritin cream outperformed hydroquinone on the basis of a Melasma Area and Severity Index (MASI) rating. The liquiritin cream was well tolerated in both studies.


 

Azelaic acid, tranexamic acid

OTC products containing azelaic acid are also effective for hyperpigmentation based on published trials in which they were compared with hydroquinone for treating melasma. In one study of 29 women with melasma cited by Dr. Woolery-Lloyd, 20% azelaic acid cream was more effective than hydroquinone 4% cream after 2 months of treatment on the basis of the mean MASI score (6.2 vs. 3.8).

The list also includes cysteamine, silymarin, and tranexamic acid.

In the case of tranexamic acid, Dr. Woolery-Lloyd cited a relatively recent study of 60 patients with melasma, comparing two strategies for applying tranexamic acid to treatment with hydroquinone over 12 weeks. Compared with 2% hydroquinone (applied nightly) or 1.8% liposomal tranexamic acid (applied twice a day), 5% tranexamic acid solution with microneedling (weekly) had a slightly greater rate of success defined as more than a 50% improvement in hyperpigmentation in an Asian population (30%, 27.8%, and 33.3%, respectively).

“Microneedling is a newer technology that appears to be effective at improving absorption,” said Dr. Woolery-Lloyd. She predicts that microneedling will be used with increasing frequency in combination with topical cosmeceuticals.

She also predicted that these topical agents will be increasingly employed in combinations as the field of cosmeceuticals becomes increasingly more sophisticated. “When it comes to skin quality, cosmeceuticals remain our first-line therapy, especially in skin of color,” she said.

The rapid growth and utility of OTC cosmeceuticals is an area that dermatologists need to be following, according to Darius Mehregan, MD, chair of the department of dermatology, Wayne State University, Detroit, who was senior author of an article published last year that reviewed the ingredients of popular OTC cosmeceuticals.

“Our patients have a great interest in cosmeceuticals and are looking to us for guidance. I think we have a responsibility to help them identify products supported by evidence and to warn them about potential side effects,” Dr. Mehregan, who was not at the meeting, said in an interview.

He agreed that the removal of hydroquinone from OTC products will create a specific need in the area of cosmeceuticals.

“Hydroquinone has for a long time been one of the most effective agents in OTC products for melasma, so patients are going to be looking for alternatives. Identifying which drugs have shown efficacy in controlled studies will be very helpful,” he said.

Dr. Woolery-Lloyd reports financial relationships with Ortho Dermatologics, L’Oréal, Galderma, Allergan, and Somabella Laboratories. Dr. Mehregan reports no potential conflicts of interest.

Cosmeceutical alternatives to hydroquinone, which is now restricted in the United States from inclusion in over-the-counter (OTC) products, are proliferating, along with new strategies to improve their efficacy, according to a report at the Skin of Color Update 2021.

“Ten or 15 years ago, I was showing a slide with five [alternatives to hydroquinone]. Now there are dozens,” reported Heather Woolery-Lloyd, MD, director of the skin of color division in the department of dermatology at the University of Miami.

The growth in alternatives to hydroquinone is timely. After threats to do so for more than a decade, the Food and Drug Administration finally banned hydroquinone from OTC products in 2020. The ban was folded into the Coronavirus Aid, Relief, and Economic Security (CARES) Act passed in March of 2020 and then implemented the following September.

Until the ban of hydroquinone, OTC products with this compound were widely sought by many individuals with darker skin tones to self-treat melasma and other forms of hyperpigmentation, according to Dr. Woolery-Lloyd. Hydroquinone is still available in prescription products, but she is often asked for OTC alternatives, and she says the list is long and getting longer.
 

Niacinamide

Detailing the products she has been recommending most frequently as substitutes, Dr. Woolery-Lloyd reported that several are supported by high quality studies. One example is niacinamide.

Of the several controlled studies she cited, one double-blind randomized trial found niacinamide to be equivalent to hydroquinone for melasma on the basis of colorimetric measures. The study compared 4% niacinamide cream applied on one side of the face with 4% hydroquinone cream applied on the other side in 27 patients with melasma. Although the proportion of responses rated good or excellent on a subjective basis was lower with niacinamide (44% vs. 55%), the difference was not statistically significant and niacinamide cream was clearly active, producing objective improvements in mast cell infiltrate and solar elastosis in melasma skin as well. Both were well tolerated.

In other studies, niacinamide has been shown to be effective in the treatment of melasma when combined with other active agents such as tranexamic acid, said Dr. Woolery-Lloyd, who added that OTC products containing niacinamide are now “among my favorites” when directing patients to cosmeceuticals for hyperpigmentation.
 

Topical vitamin C

Topical vitamin C or ascorbic acid is another. Like niacinamide, topical vitamin C has also been compared with hydroquinone in a double-blind, randomized trial. Although the niacinamide trial and this study were performed 10 or more years ago, these data have new relevance with the ban of OTC hydroquinone.

In the study, 5% ascorbic acid cream on one side of the face was compared with 4% hydroquinone cream, applied on the other side, in 16 women with melasma. Again, there were no statistical differences in colorimetric measures, but good to excellent results were reported for 93% of the sides of the face treated with hydroquinone versus 62.5% of the sides treated with vitamin C (P < .05). “Hydroquinone performed better, but the vitamin C was active and very well tolerated,” Dr. Woolery-Lloyd said.

However, the ascorbic acid cream was better tolerated, with a far lower rate of adverse events (6.2% vs. 68.7%), an advantage that makes it easy to recommend to patients, said Dr. Woolery-Lloyd, who now uses it frequently in her own practice.

Liquiritin, a licorice extract, is another lightening agent increasingly included in OTC products that she also recommends. In two older studies in medical journals published in Pakistan, both the 2% and 4% strengths of liquiritin cream outperformed hydroquinone on the basis of a Melasma Area and Severity Index (MASI) rating. The liquiritin cream was well tolerated in both studies.


 

Azelaic acid, tranexamic acid

OTC products containing azelaic acid are also effective for hyperpigmentation based on published trials in which they were compared with hydroquinone for treating melasma. In one study of 29 women with melasma cited by Dr. Woolery-Lloyd, 20% azelaic acid cream was more effective than hydroquinone 4% cream after 2 months of treatment on the basis of the mean MASI score (6.2 vs. 3.8).

The list also includes cysteamine, silymarin, and tranexamic acid.

In the case of tranexamic acid, Dr. Woolery-Lloyd cited a relatively recent study of 60 patients with melasma, comparing two strategies for applying tranexamic acid to treatment with hydroquinone over 12 weeks. Compared with 2% hydroquinone (applied nightly) or 1.8% liposomal tranexamic acid (applied twice a day), 5% tranexamic acid solution with microneedling (weekly) had a slightly greater rate of success defined as more than a 50% improvement in hyperpigmentation in an Asian population (30%, 27.8%, and 33.3%, respectively).

“Microneedling is a newer technology that appears to be effective at improving absorption,” said Dr. Woolery-Lloyd. She predicts that microneedling will be used with increasing frequency in combination with topical cosmeceuticals.

She also predicted that these topical agents will be increasingly employed in combinations as the field of cosmeceuticals becomes increasingly more sophisticated. “When it comes to skin quality, cosmeceuticals remain our first-line therapy, especially in skin of color,” she said.

The rapid growth and utility of OTC cosmeceuticals is an area that dermatologists need to be following, according to Darius Mehregan, MD, chair of the department of dermatology, Wayne State University, Detroit, who was senior author of an article published last year that reviewed the ingredients of popular OTC cosmeceuticals.

“Our patients have a great interest in cosmeceuticals and are looking to us for guidance. I think we have a responsibility to help them identify products supported by evidence and to warn them about potential side effects,” Dr. Mehregan, who was not at the meeting, said in an interview.

He agreed that the removal of hydroquinone from OTC products will create a specific need in the area of cosmeceuticals.

“Hydroquinone has for a long time been one of the most effective agents in OTC products for melasma, so patients are going to be looking for alternatives. Identifying which drugs have shown efficacy in controlled studies will be very helpful,” he said.

Dr. Woolery-Lloyd reports financial relationships with Ortho Dermatologics, L’Oréal, Galderma, Allergan, and Somabella Laboratories. Dr. Mehregan reports no potential conflicts of interest.

Cosmeceutical alternatives to hydroquinone, which is now restricted in the United States from inclusion in over-the-counter (OTC) products, are proliferating, along with new strategies to improve their efficacy, according to a report at the Skin of Color Update 2021.

“Ten or 15 years ago, I was showing a slide with five [alternatives to hydroquinone]. Now there are dozens,” reported Heather Woolery-Lloyd, MD, director of the skin of color division in the department of dermatology at the University of Miami.

The growth in alternatives to hydroquinone is timely. After threats to do so for more than a decade, the Food and Drug Administration finally banned hydroquinone from OTC products in 2020. The ban was folded into the Coronavirus Aid, Relief, and Economic Security (CARES) Act passed in March of 2020 and then implemented the following September.

Until the ban of hydroquinone, OTC products with this compound were widely sought by many individuals with darker skin tones to self-treat melasma and other forms of hyperpigmentation, according to Dr. Woolery-Lloyd. Hydroquinone is still available in prescription products, but she is often asked for OTC alternatives, and she says the list is long and getting longer.
 

Niacinamide

Detailing the products she has been recommending most frequently as substitutes, Dr. Woolery-Lloyd reported that several are supported by high quality studies. One example is niacinamide.

Of the several controlled studies she cited, one double-blind randomized trial found niacinamide to be equivalent to hydroquinone for melasma on the basis of colorimetric measures. The study compared 4% niacinamide cream applied on one side of the face with 4% hydroquinone cream applied on the other side in 27 patients with melasma. Although the proportion of responses rated good or excellent on a subjective basis was lower with niacinamide (44% vs. 55%), the difference was not statistically significant and niacinamide cream was clearly active, producing objective improvements in mast cell infiltrate and solar elastosis in melasma skin as well. Both were well tolerated.

In other studies, niacinamide has been shown to be effective in the treatment of melasma when combined with other active agents such as tranexamic acid, said Dr. Woolery-Lloyd, who added that OTC products containing niacinamide are now “among my favorites” when directing patients to cosmeceuticals for hyperpigmentation.
 

Topical vitamin C

Topical vitamin C or ascorbic acid is another. Like niacinamide, topical vitamin C has also been compared with hydroquinone in a double-blind, randomized trial. Although the niacinamide trial and this study were performed 10 or more years ago, these data have new relevance with the ban of OTC hydroquinone.

In the study, 5% ascorbic acid cream on one side of the face was compared with 4% hydroquinone cream, applied on the other side, in 16 women with melasma. Again, there were no statistical differences in colorimetric measures, but good to excellent results were reported for 93% of the sides of the face treated with hydroquinone versus 62.5% of the sides treated with vitamin C (P < .05). “Hydroquinone performed better, but the vitamin C was active and very well tolerated,” Dr. Woolery-Lloyd said.

However, the ascorbic acid cream was better tolerated, with a far lower rate of adverse events (6.2% vs. 68.7%), an advantage that makes it easy to recommend to patients, said Dr. Woolery-Lloyd, who now uses it frequently in her own practice.

Liquiritin, a licorice extract, is another lightening agent increasingly included in OTC products that she also recommends. In two older studies in medical journals published in Pakistan, both the 2% and 4% strengths of liquiritin cream outperformed hydroquinone on the basis of a Melasma Area and Severity Index (MASI) rating. The liquiritin cream was well tolerated in both studies.


 

Azelaic acid, tranexamic acid

OTC products containing azelaic acid are also effective for hyperpigmentation based on published trials in which they were compared with hydroquinone for treating melasma. In one study of 29 women with melasma cited by Dr. Woolery-Lloyd, 20% azelaic acid cream was more effective than hydroquinone 4% cream after 2 months of treatment on the basis of the mean MASI score (6.2 vs. 3.8).

The list also includes cysteamine, silymarin, and tranexamic acid.

In the case of tranexamic acid, Dr. Woolery-Lloyd cited a relatively recent study of 60 patients with melasma, comparing two strategies for applying tranexamic acid to treatment with hydroquinone over 12 weeks. Compared with 2% hydroquinone (applied nightly) or 1.8% liposomal tranexamic acid (applied twice a day), 5% tranexamic acid solution with microneedling (weekly) had a slightly greater rate of success defined as more than a 50% improvement in hyperpigmentation in an Asian population (30%, 27.8%, and 33.3%, respectively).

“Microneedling is a newer technology that appears to be effective at improving absorption,” said Dr. Woolery-Lloyd. She predicts that microneedling will be used with increasing frequency in combination with topical cosmeceuticals.

She also predicted that these topical agents will be increasingly employed in combinations as the field of cosmeceuticals becomes increasingly more sophisticated. “When it comes to skin quality, cosmeceuticals remain our first-line therapy, especially in skin of color,” she said.

The rapid growth and utility of OTC cosmeceuticals is an area that dermatologists need to be following, according to Darius Mehregan, MD, chair of the department of dermatology, Wayne State University, Detroit, who was senior author of an article published last year that reviewed the ingredients of popular OTC cosmeceuticals.

“Our patients have a great interest in cosmeceuticals and are looking to us for guidance. I think we have a responsibility to help them identify products supported by evidence and to warn them about potential side effects,” Dr. Mehregan, who was not at the meeting, said in an interview.

He agreed that the removal of hydroquinone from OTC products will create a specific need in the area of cosmeceuticals.

“Hydroquinone has for a long time been one of the most effective agents in OTC products for melasma, so patients are going to be looking for alternatives. Identifying which drugs have shown efficacy in controlled studies will be very helpful,” he said.

Dr. Woolery-Lloyd reports financial relationships with Ortho Dermatologics, L’Oréal, Galderma, Allergan, and Somabella Laboratories. Dr. Mehregan reports no potential conflicts of interest.

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

A version of this article first appeared on WebMD.com.

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

A version of this article first appeared on WebMD.com.

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

A version of this article first appeared on WebMD.com.

About 36% of transgender persons had undergone a dermatologic procedure, with hair removal by far the most common, according to the results of a recent survey.

Transfeminine persons – those assigned male at birth – were much more likely to report a previous dermatologic procedure, compared with transmasculine respondents, by a margin of 64.9%-7.5%, Laura Ragmanauskaite, MD, and associates reported.

“Hair removal was the most frequently reported procedure type, with electrolysis being more common than laser hair removal,” they said, noting that “previous research on hair removal treatments among gender minority persons did not detect differences in the use of electrolysis and laser hair removal.”

Just under one-third of all respondents (32.9%) said that they had undergone electrolysis and 4.6% reported previous laser hair removal. For electrolysis, that works out to 59.4% of transfeminine and 6.1% of transmasculine respondents, while 9.1% of all transfeminine and no transmasculine persons had received laser hair removal, Dr. Ragmanauskaite of the department of dermatology, Emory University, Atlanta, and her coauthors said.

Those who had undergone gender-affirming surgery were significantly more likely to report electrolysis (78.6%) than were persons who had received no gender-affirming surgery or hormone therapy alone (47.4%), a statistically significant difference (P < .01). All of the other, less common procedures included in the online survey – 696 responses were received from 350 transfeminine and 346 transmasculine persons participating in the Study of Transition, Outcomes, and Gender – were reported more often by the transfeminine respondents. The procedure with the closest gender distribution was body contouring, reported by nine transfeminine and six transmasculine persons, the researchers said.

Use of dermal fillers was even less common (2.8% among all respondents, all transfeminine persons), with just 11 reporting having received silicone and 8 reporting having received collagen, although the survey did not ask about how the injections were obtained. In a previous study, the prevalence of illicit filler injection in transgender women was 16.9%, they pointed out.

These types of noninvasive, gender-affirming procedures “may contribute to higher levels of self-confidence and [reduce] gender dysphoria. Future studies should examine motivations, barriers, and optimal timing” for such procedures in transgender persons, Dr. Ragmanauskaite and associates wrote.

The authors reported that they had no relevant disclosures.

[email protected]

About 36% of transgender persons had undergone a dermatologic procedure, with hair removal by far the most common, according to the results of a recent survey.

Transfeminine persons – those assigned male at birth – were much more likely to report a previous dermatologic procedure, compared with transmasculine respondents, by a margin of 64.9%-7.5%, Laura Ragmanauskaite, MD, and associates reported.

“Hair removal was the most frequently reported procedure type, with electrolysis being more common than laser hair removal,” they said, noting that “previous research on hair removal treatments among gender minority persons did not detect differences in the use of electrolysis and laser hair removal.”

Just under one-third of all respondents (32.9%) said that they had undergone electrolysis and 4.6% reported previous laser hair removal. For electrolysis, that works out to 59.4% of transfeminine and 6.1% of transmasculine respondents, while 9.1% of all transfeminine and no transmasculine persons had received laser hair removal, Dr. Ragmanauskaite of the department of dermatology, Emory University, Atlanta, and her coauthors said.

Those who had undergone gender-affirming surgery were significantly more likely to report electrolysis (78.6%) than were persons who had received no gender-affirming surgery or hormone therapy alone (47.4%), a statistically significant difference (P < .01). All of the other, less common procedures included in the online survey – 696 responses were received from 350 transfeminine and 346 transmasculine persons participating in the Study of Transition, Outcomes, and Gender – were reported more often by the transfeminine respondents. The procedure with the closest gender distribution was body contouring, reported by nine transfeminine and six transmasculine persons, the researchers said.

Use of dermal fillers was even less common (2.8% among all respondents, all transfeminine persons), with just 11 reporting having received silicone and 8 reporting having received collagen, although the survey did not ask about how the injections were obtained. In a previous study, the prevalence of illicit filler injection in transgender women was 16.9%, they pointed out.

These types of noninvasive, gender-affirming procedures “may contribute to higher levels of self-confidence and [reduce] gender dysphoria. Future studies should examine motivations, barriers, and optimal timing” for such procedures in transgender persons, Dr. Ragmanauskaite and associates wrote.

The authors reported that they had no relevant disclosures.

[email protected]

About 36% of transgender persons had undergone a dermatologic procedure, with hair removal by far the most common, according to the results of a recent survey.

Transfeminine persons – those assigned male at birth – were much more likely to report a previous dermatologic procedure, compared with transmasculine respondents, by a margin of 64.9%-7.5%, Laura Ragmanauskaite, MD, and associates reported.

“Hair removal was the most frequently reported procedure type, with electrolysis being more common than laser hair removal,” they said, noting that “previous research on hair removal treatments among gender minority persons did not detect differences in the use of electrolysis and laser hair removal.”

Just under one-third of all respondents (32.9%) said that they had undergone electrolysis and 4.6% reported previous laser hair removal. For electrolysis, that works out to 59.4% of transfeminine and 6.1% of transmasculine respondents, while 9.1% of all transfeminine and no transmasculine persons had received laser hair removal, Dr. Ragmanauskaite of the department of dermatology, Emory University, Atlanta, and her coauthors said.

Those who had undergone gender-affirming surgery were significantly more likely to report electrolysis (78.6%) than were persons who had received no gender-affirming surgery or hormone therapy alone (47.4%), a statistically significant difference (P < .01). All of the other, less common procedures included in the online survey – 696 responses were received from 350 transfeminine and 346 transmasculine persons participating in the Study of Transition, Outcomes, and Gender – were reported more often by the transfeminine respondents. The procedure with the closest gender distribution was body contouring, reported by nine transfeminine and six transmasculine persons, the researchers said.

Use of dermal fillers was even less common (2.8% among all respondents, all transfeminine persons), with just 11 reporting having received silicone and 8 reporting having received collagen, although the survey did not ask about how the injections were obtained. In a previous study, the prevalence of illicit filler injection in transgender women was 16.9%, they pointed out.

These types of noninvasive, gender-affirming procedures “may contribute to higher levels of self-confidence and [reduce] gender dysphoria. Future studies should examine motivations, barriers, and optimal timing” for such procedures in transgender persons, Dr. Ragmanauskaite and associates wrote.

The authors reported that they had no relevant disclosures.

[email protected]

To the Editor:

Lymphangioma circumscriptum (LC) is a benign malformation of the lymphatic system.¹ It is postulated to arise from abnormal lymphatic cisterns, and it grows separately from the normal lymphatic system. These cisterns are connected to malformed dermal lymphatic channels, and the contraction of smooth muscles lining cisterns will cause dilatation of connected lymphatic channels in the papillary dermis due to back pressure,^1,2 which causes a classic LC manifestation characterized by multiple translucent, sometimes red-brown, small vesicles grouped together. Lymphangioma circumscriptum can be difficult to differentiate from molluscum contagiosum (MC) due to the similar morphology.¹ We present a notable case of MC superimposed on LC.

A 6-year-old girl presented with multiple grouped, clear, vesicular papules on the right buttock of 18 months’ duration. Some of the papules showed tiny whitish pearl-like particles on the top (Figure 1). Similar lesions were not present elsewhere on the body. She had no underlying disease and did not have a history of procedure, edema, or malformation of the lower extremities. Histopathology from one of the lesions showed dilated cystic lymphatic spaces in the papillary dermis lined with flattened endothelium and cup-shaped downward proliferation of the epidermis with presence of large intracytoplasmic inclusion bodies—features of both LC and MC (Figure 2). We waited 4 additional months for the MC lesions to self-resolve, but they persisted. The patient’s mother strongly requested for their removal, and the residual MC lesions were carefully removed by CO₂ laser. To prevent unnecessary physical damage to underlying LC lesions and minimize scarring, we opted to use the CO₂ laser and not simple curettage. She currently is under periodic observation with no signs of clinical recurrence of MC, but the LC lesions naturally persisted.

Due to its vesicular and sometimes warty appearance, LC can sometimes be hard to differentiate from MC. In one report, a vesicular plaquelike lesion on the trunk initially was misdiagnosed and treated as MC but was histologically confirmed as LC several years later.³ Our case demonstrates the coexistence of MC and LC. Although this phenomenon may be coincidental, we have not noticed any additional MC lesions on the body and MC only existed over the LC lesions, implying a possible pathophysiologic relationship. It is unlikely that MC might have preceded the development of LC. Although acquired LC exists, it has mostly been reported in the genital region of patients with conditions leading to lymphatic obstruction such as surgery, radiation therapy, malignancy, or serious infections.⁴ Because our patient developed lesions at an early age without any remarkable medical history, it is likely that she had congenital LC that was secondarily infected by the MC virus. Vesicular lesions in LC are known to rupture easily and may serve as a vulnerable entry site for pathogens. Subsequent secondary bacterial infections are common, with Staphylococcus aureus being the most prominent entity.¹ However, secondary viral infection rarely is reported. It is possible that the abnormally dilated lymphatic channels of LC that lack communication with the normal lymphatic system have contributed to an LC site-specific vulnerability to MC virus. Further studies and subsequent reports are required to confirm this hypothesis.

To the Editor:

Lymphangioma circumscriptum (LC) is a benign malformation of the lymphatic system.¹ It is postulated to arise from abnormal lymphatic cisterns, and it grows separately from the normal lymphatic system. These cisterns are connected to malformed dermal lymphatic channels, and the contraction of smooth muscles lining cisterns will cause dilatation of connected lymphatic channels in the papillary dermis due to back pressure,^1,2 which causes a classic LC manifestation characterized by multiple translucent, sometimes red-brown, small vesicles grouped together. Lymphangioma circumscriptum can be difficult to differentiate from molluscum contagiosum (MC) due to the similar morphology.¹ We present a notable case of MC superimposed on LC.

A 6-year-old girl presented with multiple grouped, clear, vesicular papules on the right buttock of 18 months’ duration. Some of the papules showed tiny whitish pearl-like particles on the top (Figure 1). Similar lesions were not present elsewhere on the body. She had no underlying disease and did not have a history of procedure, edema, or malformation of the lower extremities. Histopathology from one of the lesions showed dilated cystic lymphatic spaces in the papillary dermis lined with flattened endothelium and cup-shaped downward proliferation of the epidermis with presence of large intracytoplasmic inclusion bodies—features of both LC and MC (Figure 2). We waited 4 additional months for the MC lesions to self-resolve, but they persisted. The patient’s mother strongly requested for their removal, and the residual MC lesions were carefully removed by CO₂ laser. To prevent unnecessary physical damage to underlying LC lesions and minimize scarring, we opted to use the CO₂ laser and not simple curettage. She currently is under periodic observation with no signs of clinical recurrence of MC, but the LC lesions naturally persisted.

Due to its vesicular and sometimes warty appearance, LC can sometimes be hard to differentiate from MC. In one report, a vesicular plaquelike lesion on the trunk initially was misdiagnosed and treated as MC but was histologically confirmed as LC several years later.³ Our case demonstrates the coexistence of MC and LC. Although this phenomenon may be coincidental, we have not noticed any additional MC lesions on the body and MC only existed over the LC lesions, implying a possible pathophysiologic relationship. It is unlikely that MC might have preceded the development of LC. Although acquired LC exists, it has mostly been reported in the genital region of patients with conditions leading to lymphatic obstruction such as surgery, radiation therapy, malignancy, or serious infections.⁴ Because our patient developed lesions at an early age without any remarkable medical history, it is likely that she had congenital LC that was secondarily infected by the MC virus. Vesicular lesions in LC are known to rupture easily and may serve as a vulnerable entry site for pathogens. Subsequent secondary bacterial infections are common, with Staphylococcus aureus being the most prominent entity.¹ However, secondary viral infection rarely is reported. It is possible that the abnormally dilated lymphatic channels of LC that lack communication with the normal lymphatic system have contributed to an LC site-specific vulnerability to MC virus. Further studies and subsequent reports are required to confirm this hypothesis.

To the Editor:

Lymphangioma circumscriptum (LC) is a benign malformation of the lymphatic system.¹ It is postulated to arise from abnormal lymphatic cisterns, and it grows separately from the normal lymphatic system. These cisterns are connected to malformed dermal lymphatic channels, and the contraction of smooth muscles lining cisterns will cause dilatation of connected lymphatic channels in the papillary dermis due to back pressure,^1,2 which causes a classic LC manifestation characterized by multiple translucent, sometimes red-brown, small vesicles grouped together. Lymphangioma circumscriptum can be difficult to differentiate from molluscum contagiosum (MC) due to the similar morphology.¹ We present a notable case of MC superimposed on LC.

A 6-year-old girl presented with multiple grouped, clear, vesicular papules on the right buttock of 18 months’ duration. Some of the papules showed tiny whitish pearl-like particles on the top (Figure 1). Similar lesions were not present elsewhere on the body. She had no underlying disease and did not have a history of procedure, edema, or malformation of the lower extremities. Histopathology from one of the lesions showed dilated cystic lymphatic spaces in the papillary dermis lined with flattened endothelium and cup-shaped downward proliferation of the epidermis with presence of large intracytoplasmic inclusion bodies—features of both LC and MC (Figure 2). We waited 4 additional months for the MC lesions to self-resolve, but they persisted. The patient’s mother strongly requested for their removal, and the residual MC lesions were carefully removed by CO₂ laser. To prevent unnecessary physical damage to underlying LC lesions and minimize scarring, we opted to use the CO₂ laser and not simple curettage. She currently is under periodic observation with no signs of clinical recurrence of MC, but the LC lesions naturally persisted.

Due to its vesicular and sometimes warty appearance, LC can sometimes be hard to differentiate from MC. In one report, a vesicular plaquelike lesion on the trunk initially was misdiagnosed and treated as MC but was histologically confirmed as LC several years later.³ Our case demonstrates the coexistence of MC and LC. Although this phenomenon may be coincidental, we have not noticed any additional MC lesions on the body and MC only existed over the LC lesions, implying a possible pathophysiologic relationship. It is unlikely that MC might have preceded the development of LC. Although acquired LC exists, it has mostly been reported in the genital region of patients with conditions leading to lymphatic obstruction such as surgery, radiation therapy, malignancy, or serious infections.⁴ Because our patient developed lesions at an early age without any remarkable medical history, it is likely that she had congenital LC that was secondarily infected by the MC virus. Vesicular lesions in LC are known to rupture easily and may serve as a vulnerable entry site for pathogens. Subsequent secondary bacterial infections are common, with Staphylococcus aureus being the most prominent entity.¹ However, secondary viral infection rarely is reported. It is possible that the abnormally dilated lymphatic channels of LC that lack communication with the normal lymphatic system have contributed to an LC site-specific vulnerability to MC virus. Further studies and subsequent reports are required to confirm this hypothesis.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

To the Editor:

A 67-year-old man with diabetes mellitus was admitted to the hospital for exacerbation of congestive heart failure and atrial flutter with rapid ventricular response. He subsequently developed a non-ST segment elevation myocardial infarction and was started on subcutaneous enoxaparin 110 mg twice daily. On day 9 of hospitalization, small “blood blisters” on the legs were noted by the nurse, and dermatology was consulted.

Physical examination revealed tense hemorrhagic bullae with erythematous haloes scattered over the arms and legs and to a lesser extent on the trunk. The bullae were most concentrated at the surrounding subcutaneous injection sites of insulin and enoxaparin with secondary bruising (Figure 1). The lesions also were present on the legs, where pitting edema and capillaritis also were appreciated (Figure 2).

Laboratory workup for heparin-induced thrombocytopenia was negative. A diagnosis of enoxaparin-associated hemorrhagic bullae was made. Biopsy was recommended, but the patient declined based on anecdotal reports that the bullae typically self-resolve.

The enoxaparin was discontinued 7 days after the dermatology consultation, and the patient was transitioned to apixaban. A review of the medical record during the dermatology consultation revealed he had been on aspirin (81–385 mg/d) for 13 years prior to admission and had received prophylactic enoxaparin (40 mg/d) while hospitalized 2 and 7 years prior to the current episode of hemorrhagic bullae.

The patient declined outpatient dermatology follow-up; however, his cardiologist noted that the skin lesions had resolved at a 3-week postdischarge appointment. Approximately 5 months after discharge, the patient was re-treated by the cardiologist with enoxaparin 110 mg twice daily for 3 days to bridge to warfarin after he developed a deep vein thrombosis while taking apixaban. He did not develop hemorrhagic bullae upon retreatment with enoxaparin.

Heparin-induced hemorrhagic bullous dermatosis (HBD) has been associated with administration of both unfractionated and low-molecular-weight heparin.¹ The condition typically develops 5 to 21 days after initiation of heparin as asymptomatic, purple-to-black bullae, sometimes with an erythematous halo.^2,3 The arms and legs are the most common location, but the exact pathogenesis of the lesions remains unknown.^3,4 Most cases resolve within weeks of discontinuing heparin, although some reports have suggested that discontinuation is unnecessary.^3,4

Histopathologic analysis shows intraepidermal or subepidermal bullae with red blood cells and fibrin in the absence of vasculitis and intravascular thrombi.^1,4 Immunofluorescence studies are negative.³ In a comprehensive review of HBD, the investigators hypothesized that the pathogenesis may be related to noninflammatory to pauci-inflammatory activation of basement membrane zone proteases or possibly epithelial or endothelial fragility in conjunction with trauma that causes disruption of the vascular endothelium (eg, subcutaneous injections, vasculitis).⁴

Our case is of particular interest because the bullae were strikingly limited to sites of subcutaneous injection and surrounding areas along with coexistent endothelial pathology on the lower legs (capillaritis and pitting edema). These clinical observations support trauma from the injections and altered endothelia as pathogenetic factors in HBD.

Of interest, our patient had 2 prior hospitalizations during which he received prophylactic enoxaparin and did not develop hemorrhagic bullae. Furthermore, repeat exposure to therapeutic dosing of enoxaparin with a shorter duration did not result in recurrence of HBD. This suggests that heparin dosing and duration of therapy also might be involved in the development of HBD.

Our hope is that future reports of HBD will address the presence or absence of coexistent cutaneous pathology, such as edema, stasis dermatitis, bruising, and capillaritis, along with heparin dosing, duration, and prior exposure to heparin treatment so that risk factors and pathogenesis can be further investigated. We also agree with Snow et al⁴ that HBD should be included as an outcome in future trials of heparin therapy.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

Cutaneous granulomatous diseases encompass many entities that are skin-limited or systemic. The prototypical cutaneous granuloma is a painless, rounded, well-defined, red-pink or flesh-colored papule¹ and is smooth, owing to minimal epidermal involvement. Examples of conditions that present with such lesions include granulomatous periorificial dermatitis (GPD), granulomatous rosacea (GR), lupus miliaris disseminatus faciei (LMDF), and papular sarcoidosis. These entities commonly are seen on the face and can be a source of distress to patients when they are extensive. Several reports have raised the possibility that these conditions lie on a spectrum.^2-4 We present 2 cases of patients with facial papular granulomas, discuss potential causes of the lesions, review historical aspects from the literature, and highlight the challenges that these lesions can pose to the clinician.

Case Reports

Patient 1—A 10-year-old Ethiopian girl with a history of atopic dermatitis presented with a facial rash of 4 months’ duration. Her pediatrician initially treated the rash as pityriasis alba and prescribed hydrocortisone cream. Two months into treatment, the patient developed an otherwise asymptomatic, unilateral, papular dermatosis on the right cheek. She subsequently was switched to treatment with benzoyl peroxide and topical clindamycin, which she had been using for 2 months with no improvement at the time of the current presentation. The lesions then spread bilaterally and periorally.

At the current presentation, physical examination demonstrated fine, diffuse, follicular-based, flesh-colored papules over both cheeks, the right side of the nose, and the perioral region (Figure 1). A biopsy of a papular lesion from the right cheek revealed well-formed, noncaseating granulomas in the superficial and mid dermis with an associated lymphocytic infiltrate (Figure 2). No organisms were identified on acid-fast, Fite, or periodic acid–Schiff staining. A tuberculin skin test was negative. A chest radiograph showed small calcified hilar lymph nodes bilaterally. Pulmonary function tests were unremarkable. Calcium and angiotensin-converting enzyme levels were normal.

The patient denied any fever, chills, hemoptysis, cough, dyspnea, lymphadenopathy, scleral or conjunctival pain or erythema, visual disturbances, or arthralgias. Hydroxychloroquine 200 mg twice daily was started with minimal improvement after 5 months. Methotrexate 20 mg once weekly was then added. Topical fluocinonide 0.05% also was started at this time, as the patient had required several prednisone tapers over the past 3 months for symptomatic relief. The lesions improved minimally after 5 more months of treatment, at which time she had developed inflammatory papules, pustules, and open comedones in the same areas as well as the glabella.

Repeat biopsy of a papular lesion demonstrated noncaseating granulomas and an associated chronic lymphocytic infiltrate in a follicular and perifollicular distribution (Figure 3). Biopsy of a pustule demonstrated acute Demodex folliculitis. Fluocinonide was stopped, and anti-mite therapy with ivermectin, permethrin cream 5%, and selenium sulfide lotion 2.5% was started, with good response from the pustular lesions.

The patient continued taking methotrexate 20 mg once weekly during this time, with improvement in the papular lesions. She discontinued methotrexate after 12 months with complete resolution. At follow-up 12 months after stopping the methotrexate (roughly 2 years after initial presentation), she showed sustained resolution, with small pitted scars on both cheeks and the nasal tip.

Patient 2—A 33-year-old Ethiopian woman presented with a facial rash of 15 years’ duration. The lesions had been accumulating slowly and were asymptomatic. Physical examination revealed multiple follicular-based, flesh-colored, and erythematous papules on the cheeks, chin, perioral area, and forehead (Figure 4). There were no pustules or telangiectasias. Treatment with tretinoin cream 0.05% for 6 months offered minimal relief.

Biopsy of a papule from the left mandible showed superficial vascular telangiectasias, noncaseating granulomas comprising epithelioid histiocytes and lymphocytes in the superficial dermis, and a perifollicular lymphocytic infiltrate (Figure 5). No organisms were identified on Fite or Gomori methenamine silver staining.

Comment

The first step in differentiating cutaneous granulomatous lesions should be to distinguish infectious from noninfectious causes.¹ Noninfectious cutaneous granulomas can appear nearly anywhere; however, certain processes have a predilection for the face, including GPD, GR, LMDF, and papular sarcoidosis.^5-7 These conditions generally present with papular granulomas with features as described above.

Granulomatous Periorificial Dermatitis—In 1970, Gianotti and colleagues⁸ briefly described the first possible cases of GPD in 5 children. The eruption comprised numerous yellow, dome-shaped papules in a mostly perioral distribution. Tuberculin and the Kveim tests were nonreactive; histopathology was described as sarcoid-type and not necessarily follicular or perifollicular.⁸ In 1974, Marten et al⁹ described 22 Afro-Caribbean children with flesh-colored, papular eruptions on the face that did not show histologic granulomatous changes but were morphologically similar to the reports by Gianotti et al.⁸ By 1989, Frieden and colleagues¹⁰ described this facial eruption as “granulomatous perioral dermatitis in children”. Additionally, the investigators observed granulomatous infiltrates in a perifollicular distribution and suggested follicular disruption as a possible cause. It was clear from the case discussions that these eruptions were not uncommonly diagnosed as papular sarcoidosis.¹⁰ The following year, Williams et al¹¹ reported 5 cases of similar papular eruptions in 5 Afro-Caribbean children, coining the term facial Afro-Caribbean eruption.¹¹ Knautz and Lesher¹² referred to this entity as “childhood GPD” in 1996 to avoid limiting the diagnosis to Afro-Caribbean patients and to a perioral distribution; this is the most popular current terminology.¹² Since then, reports of extrafacial involvement and disease in adults have been published.^13,14

Granulomatous periorificial dermatitis often is seen in the perinasal, periocular, and perioral regions of the face.² It is associated with topical steroid exposure.⁵ Histologically, noncaseating granulomas around the upper half of undisrupted hair follicles with a lymphocytic infiltrate are typical.¹³ Treatment should begin with cessation of any topical steroids; first-line agents are oral tetracycline or macrolide antibiotics.⁵ These agents can be used alone or in combination with topical erythromycin, metronidazole, or sulfur-based lotions.¹³ Rarely, GPD presents extrafacially.¹³ Even so, it usually resolves within 2 weeks to 6 months, especially with therapy; scarring is unusual.^5,13,15

Granulomatous Rosacea—A report in the early 20th century described patients with tuberculoid granulomas resembling papular rosacea; the initial belief was that this finding represented a rosacealike tuberculid eruption.⁵ However, this belief was questioned by Snapp,¹⁶ among others, who demonstrated near universal lack of reactivity to tuberculin among 20 of these patients in 1949; more recent evidence has substantiated these findings.¹⁷ Still, Snapp¹⁶ postulated that these rosacealike granulomatous lesions were distinct from classic rosacea because they lacked vascular symptoms and pustules and were recalcitrant to rosacea treatment modalities.

In 1970, Mullanax and colleagues¹⁸ introduced the term granulomatous rosacea, reiterating that this entity was not tuberculous. They documented papulopustular lesions as well as telangiectasias, raising the possibility that GR does overlap with acne rosacea. More recent studies have established the current theory that GR is a histologic variant of acne rosacea because, in addition to typical granulomatous papules, its microscopic features can be seen across subtypes of acne rosacea.^19,20

Various causes have been proposed for GR. Demodex mites have been reported in association with GR for nearly 30 years.^19,20 In the past 10 years, molecular studies have started to define the role of metalloproteinases, UV radiation, and cutaneous peptides in the pathogenesis of acne rosacea and GR.^21,22

Granulomatous rosacea typically is seen in middle-aged women.^20,23 Hallmarks of rosacea, such as facial erythema, flushing, telangiectasias, pustules, and rhinophyma, are not always present in GR.^5,20,23 Lesions usually are distributed around the central face, although extension to the cheeks, total facial involvement, and extrafacial lesions are possible.^5,20 Histologically, perifollicular and follicular-based noncaseating granulomas with dilatation of the dermal papillary vasculature are seen.^17,23 As a whole, rosacea is comparatively uncommon in dark-skinned patients; when it does occur, GR is a frequent presentation.²⁴

First-line treatment for GR is tetracycline antibiotics.⁵ Unresponsive cases have been treated—largely anecdotally—with topical modalities (eg, metronidazole, steroids, immunomodulators), systemic agents (eg, dapsone, erythromycin, isotretinoin), and other therapies.⁵ Granulomatous rosacea tends to have a chronic course.^5,23

Lupus Miliaris Disseminatus Faciei—Classic LMDF demonstrates caseating perifollicular granulomas histologically.^6,17,25 Lesions tend to appear on the central face, particularly the eyelids, and can be seen extrafacially.^3,6,25,26 Although LMDF originally was categorized as a tuberculid eruption, this no longer is thought to be the case.²⁷ It is now regarded by some as a variant of GR²⁵; however, LMDF responds poorly to tetracyclines, is more common in males, and lacks rosacealike vascular abnormalities, leading some to question this association.^3,6,17 In the past 20 years, some have proposed renaming LMDF to better reflect its clinical course and to consider it independent of tuberculosis and GR.²⁸ It usually resolves spontaneously after 1 to 3 years, leaving pitted scars.^3,6

Papular Sarcoidosis—The first potential documented case of sarcoidosis was by Hutchinson²⁹ in 1869 in a patient seen in London. The author labeled purple plaques on the index patient’s legs and hands as “livid papillary psoriasis.” In 1889, Besnier³⁰ described a patient with violaceous swellings on the nose, ears, and fingers, which he called “lupus pernio”; his contemporary, Tenneson,³¹ published a case of lupus pernio and described its histologic profile as comprising epithelioid cells and giant cells. It was not until 1899 that the term sarkoid was used to describe these cutaneous lesions by Boeck,³² who thought they were reminiscent of sarcoma. In 1915, Kuznitsky and Bittorf³³ described a patient with cutaneous lesions histologically consistent with Boeck’s sarkoid but additionally with hilar lymphadenopathy and pulmonary infiltrates. Around 1916 or 1917, Schaumann³⁴ described patients with cutaneous lesions and additionally with involvement of pulmonary, osseous, hepatosplenic, and tonsillar tissue. These reports are among the first to recognize the multisystemic nature of sarcoidosis. The first possible case of childhood sarcoidosis might have been reported by Osler³⁵ in the United States in 1898.

In the past century or so, an ongoing effort by researchers has focused on identifying etiologic triggers for sarcoidosis. Microbial agents have been considered in this role, with Mycobacterium and Propionibacterium organisms the most intensively studied; the possibility that foreign material contributes to the formation of granulomas also has been raised.³⁶ Current models of the pathogenesis of sarcoidosis involve an interplay between the immune system in genetically predisposed patients and an infection that leads to a hyperimmune type 1 T–helper cell response that clears the infection but not antigens generated by the microbes and the acute host response, including proteins such as serum amyloid A and vimentin.^36,37 These antigens aggregate and serve as a nidus for granuloma formation and maintenance long after infection has resolved.

Cutaneous lesions of sarcoidosis include macules, papules, plaques, and lupus pernio, as well as lesions arising within scars or tattoos, with many less common presentations.^7,38 Papular sarcoidosis is common on the face but also can involve the extremities.^4,7 Strictly, at least 2 organ systems must be involved to diagnose sarcoidosis, but this is debatable.^4,7 Among 41 patients with cutaneous sarcoidosis, 24 (58.5%) had systemic disease; cutaneous lesions were the presenting sign in 87.5% (21/24) of patients.³⁸ Histologic analysis, regardless of the lesion, usually shows noncaseating so-called “naked” granulomas, which have minimal lymphocytic infiltrate associated with the epithelioid histiocytes.^38,39 Perifollicular granulomas are possible but unusual.⁴⁰

Treatment depends on the extent of cutaneous and systemic involvement. Pharmacotherapeutic modalities include topical steroids, immunomodulators, and retinoids; systemic immunomodulators and immunosuppressants; and biologic agents.⁷ Isolated cutaneous sarcoidosis, particularly the papular variant, usually is associated with acute disease lasting less than 2 years, with resolution of skin lesions.^7,38 That said, a recent report suggested that cutaneous sarcoidosis can progress to multisystemic disease as long as 7 years after the initial diagnosis.⁴¹

Clinical and Histologic Overlap—Despite this categorization of noninfectious facial granulomatous conditions, each has some clinical and histologic overlap with the others, which must be considered when encountering a granulomatous facial dermatosis. Both GPD and GR tend to present with lesions near the eyes, mouth, and nose, although GR can extend to lateral aspects of the face, below the mandible, and the forehead and has different demographic features.^15,20,23 Granulomas in both GPD and GR generally are noncaseating and form in a follicular or perifollicular distribution within the dermis.^2,15,23 Lupus miliaris disseminatus faciei and GR share a similar facial distribution in some cases.^17,20 Even papular cutaneous sarcoidosis has masqueraded as GR clinically and histologically.⁴

Diagnostic and Treatment Difficulty—Our cases illustrate the range of difficulty in evaluating and managing patients with facial papular granulomas. On one hand, our adult patient’s clinical and histologic findings were highly consistent with GR; on the other hand, our younger patient had clinicopathologic features of both sarcoidosis and GPD at varying times. Both conditions are more common in dark-skinned patients.^11,42

Juvenile sarcoidosis is comparatively rare, with a reported annual incidence of 0.22 to 0.27 for every 100,000 children younger than 15 years; however, juvenile sarcoidosis commonly presents around 8 to 15 years of age.⁴³

It is unusual for sarcoid granulomas to be isolated to the skin, much less to the face.^4,7,43,44 Patient 1 initially presented in this manner and lacked convincing laboratory or radiographic evidence of systemic sarcoidosis. Bilateral hilar calcifications in sarcoidosis are more typical among adults after 5 to 20 years; there were no signs or symptoms of active infection that could account for the pulmonary and cutaneous lesions.⁴⁵

The presence of perifollicular granulomas with associated lymphocytic infiltrates on repeat biopsy, coupled with the use of topical steroids, made it difficult to rule out a contribution by GPD to her clinical course. That her lesions resolved with pitted scarring while she was taking methotrexate and after topical steroids had been stopped could be the result of successful management or spontaneous resolution of her dermatosis; both papular sarcoidosis and GPD tend to have a self-limited course.^7,13

Conclusion

We present 2 cases of papular facial granulomas in patients with similar skin types who had different clinical courses. Evaluation of such lesions remains challenging given the similarity between specific entities that present in this manner. Certainly, it is reasonable to consider a spectrum upon which all of these conditions fall, in light of the findings of these cases and those reported previously.

The Diagnosis: Striated Muscle Hamartoma

Histopathologic evaluation revealed a dome-shaped papule with a center composed of mature striated muscle bundles, vellus hairs, sebaceous lobules, and nerve twigs (Figure) consistent with a diagnosis of striated muscle hamartoma (SMH).

Striated muscle hamartoma was first described in 1986 by Hendrick et al1 with 2 cases in neonates. Biopsies of the lesions taken from the upper lip and sternum showed a characteristic histology consisting of dermal striated muscle fibers and nerve bundles in the central core of the papules associated with a marked number of adnexa. In 1989, the diagnosis of rhabdomyomatous mesenchymal hamartoma was described, which showed similar findings.² Cases reported since these entities were discovered have used the terms striated muscle hamartoma and rhabdomyomatous mesenchymal hamartoma interchangeably.³

Most commonly found on the head and neck, SMH has now been observed in diverse locations including the sternum, hallux, vagina, and oral cavity.^1-15 Many reported cases describe lesions around or in the nose.^4,7,8 Multiple congenital anomalies have been described alongside SMH and may be associated with this entity including amniotic bands, cleft lip and palate, coloboma, and Delleman syndrome.^1,3,4 Almost all of the lesions present as a sessile or pedunculated papule, polyp, nodule, or plaque measuring from 0.3 cm up to 4.9 cm and typically are present since birth.^3,5,15 However, there are a few cases of lesions presenting in adults with no prior history.^5,6,15

Microscopically, SMH is defined by a dermal lesion with a core comprised of mature skeletal muscle admixed with adipose tissue, adnexa, nerve bundles, and fibrovascular tissue.¹ There are other entities that should be considered before making the diagnosis of SMH. Other hamartomas such as accessory tragus, connective tissue nevus, fibrous hamartoma of infancy, and nevus lipomatosis may present similarly; however, these lesions classically lack skeletal muscle. Benign triton tumors, or neuromuscular hamartomas, are rare lesions composed of skeletal muscle and abundant, intimately associated neural tissue. Neuromuscular hamartomas frequently involve large nerves.¹⁶ Rhabdomyomas also should be considered. Adult rhabdomyomas are composed of eosinophilic polygonal cells with granular cytoplasm and occasional cross-striations. Fetal rhabdomyomas have multiple histologic types and are defined by a variable myxoid stroma, eosinophilic spindled cells, and rhabdomyocytes in various stages of maturity. Genital rhabdomyomas histopathologically appear similar to fetal rhabdomyomas but are confined to the genital region. The skeletal muscle present in rhabdomyomas typically is less differentiated.¹⁷ TMature skeletal bundles should be a dominant component of the lesion before diagnosing SMH.

Typically presenting as congenital lesions in the head and neck region, papules with a dermal core of mature skeletal muscle associated with adnexa and nerve twigs should prompt consideration of a diagnosis of SMH or rhabdomyomatous mesenchymal hamartoma. These lesions are benign and usually are cured with complete excision.

The Diagnosis: Striated Muscle Hamartoma

Histopathologic evaluation revealed a dome-shaped papule with a center composed of mature striated muscle bundles, vellus hairs, sebaceous lobules, and nerve twigs (Figure) consistent with a diagnosis of striated muscle hamartoma (SMH).

Striated muscle hamartoma was first described in 1986 by Hendrick et al1 with 2 cases in neonates. Biopsies of the lesions taken from the upper lip and sternum showed a characteristic histology consisting of dermal striated muscle fibers and nerve bundles in the central core of the papules associated with a marked number of adnexa. In 1989, the diagnosis of rhabdomyomatous mesenchymal hamartoma was described, which showed similar findings.² Cases reported since these entities were discovered have used the terms striated muscle hamartoma and rhabdomyomatous mesenchymal hamartoma interchangeably.³

Most commonly found on the head and neck, SMH has now been observed in diverse locations including the sternum, hallux, vagina, and oral cavity.^1-15 Many reported cases describe lesions around or in the nose.^4,7,8 Multiple congenital anomalies have been described alongside SMH and may be associated with this entity including amniotic bands, cleft lip and palate, coloboma, and Delleman syndrome.^1,3,4 Almost all of the lesions present as a sessile or pedunculated papule, polyp, nodule, or plaque measuring from 0.3 cm up to 4.9 cm and typically are present since birth.^3,5,15 However, there are a few cases of lesions presenting in adults with no prior history.^5,6,15

Microscopically, SMH is defined by a dermal lesion with a core comprised of mature skeletal muscle admixed with adipose tissue, adnexa, nerve bundles, and fibrovascular tissue.¹ There are other entities that should be considered before making the diagnosis of SMH. Other hamartomas such as accessory tragus, connective tissue nevus, fibrous hamartoma of infancy, and nevus lipomatosis may present similarly; however, these lesions classically lack skeletal muscle. Benign triton tumors, or neuromuscular hamartomas, are rare lesions composed of skeletal muscle and abundant, intimately associated neural tissue. Neuromuscular hamartomas frequently involve large nerves.¹⁶ Rhabdomyomas also should be considered. Adult rhabdomyomas are composed of eosinophilic polygonal cells with granular cytoplasm and occasional cross-striations. Fetal rhabdomyomas have multiple histologic types and are defined by a variable myxoid stroma, eosinophilic spindled cells, and rhabdomyocytes in various stages of maturity. Genital rhabdomyomas histopathologically appear similar to fetal rhabdomyomas but are confined to the genital region. The skeletal muscle present in rhabdomyomas typically is less differentiated.¹⁷ TMature skeletal bundles should be a dominant component of the lesion before diagnosing SMH.

Typically presenting as congenital lesions in the head and neck region, papules with a dermal core of mature skeletal muscle associated with adnexa and nerve twigs should prompt consideration of a diagnosis of SMH or rhabdomyomatous mesenchymal hamartoma. These lesions are benign and usually are cured with complete excision.

The Diagnosis: Striated Muscle Hamartoma

Histopathologic evaluation revealed a dome-shaped papule with a center composed of mature striated muscle bundles, vellus hairs, sebaceous lobules, and nerve twigs (Figure) consistent with a diagnosis of striated muscle hamartoma (SMH).

Striated muscle hamartoma was first described in 1986 by Hendrick et al1 with 2 cases in neonates. Biopsies of the lesions taken from the upper lip and sternum showed a characteristic histology consisting of dermal striated muscle fibers and nerve bundles in the central core of the papules associated with a marked number of adnexa. In 1989, the diagnosis of rhabdomyomatous mesenchymal hamartoma was described, which showed similar findings.² Cases reported since these entities were discovered have used the terms striated muscle hamartoma and rhabdomyomatous mesenchymal hamartoma interchangeably.³

Most commonly found on the head and neck, SMH has now been observed in diverse locations including the sternum, hallux, vagina, and oral cavity.^1-15 Many reported cases describe lesions around or in the nose.^4,7,8 Multiple congenital anomalies have been described alongside SMH and may be associated with this entity including amniotic bands, cleft lip and palate, coloboma, and Delleman syndrome.^1,3,4 Almost all of the lesions present as a sessile or pedunculated papule, polyp, nodule, or plaque measuring from 0.3 cm up to 4.9 cm and typically are present since birth.^3,5,15 However, there are a few cases of lesions presenting in adults with no prior history.^5,6,15

Microscopically, SMH is defined by a dermal lesion with a core comprised of mature skeletal muscle admixed with adipose tissue, adnexa, nerve bundles, and fibrovascular tissue.¹ There are other entities that should be considered before making the diagnosis of SMH. Other hamartomas such as accessory tragus, connective tissue nevus, fibrous hamartoma of infancy, and nevus lipomatosis may present similarly; however, these lesions classically lack skeletal muscle. Benign triton tumors, or neuromuscular hamartomas, are rare lesions composed of skeletal muscle and abundant, intimately associated neural tissue. Neuromuscular hamartomas frequently involve large nerves.¹⁶ Rhabdomyomas also should be considered. Adult rhabdomyomas are composed of eosinophilic polygonal cells with granular cytoplasm and occasional cross-striations. Fetal rhabdomyomas have multiple histologic types and are defined by a variable myxoid stroma, eosinophilic spindled cells, and rhabdomyocytes in various stages of maturity. Genital rhabdomyomas histopathologically appear similar to fetal rhabdomyomas but are confined to the genital region. The skeletal muscle present in rhabdomyomas typically is less differentiated.¹⁷ TMature skeletal bundles should be a dominant component of the lesion before diagnosing SMH.

Typically presenting as congenital lesions in the head and neck region, papules with a dermal core of mature skeletal muscle associated with adnexa and nerve twigs should prompt consideration of a diagnosis of SMH or rhabdomyomatous mesenchymal hamartoma. These lesions are benign and usually are cured with complete excision.

Key clinical point: In patients with psoriatic arthritis (PsA), 5 mg tofacitinib twice a day showed numerically better response with background ≥15 mg methotrexate per week. A twice daily dose of 10 mg tofacitinib, however, showed better response with background ≤15 mg methotrexate per week.

Major finding: In the 5 mg tofacitinib group, 51.4% vs. 47.4% of patients receiving background ≥15 mg methotrexate per week vs. ≤15 mg per week achieved American College of Rheumatology (ACR20) response at 3 months. However, in the 10 mg tofacitinib group, 54.9% vs. 51.8% of patients receiving ≤15 mg methotrexate per week vs. ≥15 mg per week achieved ACR20. No new safety risks were identified.

Study details: Findings are from pooled, post hoc exploratory analysis of 2 phase 3 trials, OPAL Broaden and OPAL Beyond, including 556 patients with active PsA randomly assigned to tofacitinib (5 mg or 10 mg twice daily) or placebo, with stable methotrexate.

Disclosures: This study was funded by Pfizer. Some of the authors reported ties with various sources, including Pfizer. C Wang and L Takiya declared being employees and shareholders of Pfizer.

Source: Kivitz AJ et al. Clin Rheumatol. 2021 Sep 12. doi: 10.1007/s10067-021-05894-2.

Key clinical point: In patients with psoriatic arthritis (PsA), 5 mg tofacitinib twice a day showed numerically better response with background ≥15 mg methotrexate per week. A twice daily dose of 10 mg tofacitinib, however, showed better response with background ≤15 mg methotrexate per week.

Major finding: In the 5 mg tofacitinib group, 51.4% vs. 47.4% of patients receiving background ≥15 mg methotrexate per week vs. ≤15 mg per week achieved American College of Rheumatology (ACR20) response at 3 months. However, in the 10 mg tofacitinib group, 54.9% vs. 51.8% of patients receiving ≤15 mg methotrexate per week vs. ≥15 mg per week achieved ACR20. No new safety risks were identified.

Study details: Findings are from pooled, post hoc exploratory analysis of 2 phase 3 trials, OPAL Broaden and OPAL Beyond, including 556 patients with active PsA randomly assigned to tofacitinib (5 mg or 10 mg twice daily) or placebo, with stable methotrexate.

Disclosures: This study was funded by Pfizer. Some of the authors reported ties with various sources, including Pfizer. C Wang and L Takiya declared being employees and shareholders of Pfizer.

Source: Kivitz AJ et al. Clin Rheumatol. 2021 Sep 12. doi: 10.1007/s10067-021-05894-2.

Key clinical point: In patients with psoriatic arthritis (PsA), 5 mg tofacitinib twice a day showed numerically better response with background ≥15 mg methotrexate per week. A twice daily dose of 10 mg tofacitinib, however, showed better response with background ≤15 mg methotrexate per week.

Major finding: In the 5 mg tofacitinib group, 51.4% vs. 47.4% of patients receiving background ≥15 mg methotrexate per week vs. ≤15 mg per week achieved American College of Rheumatology (ACR20) response at 3 months. However, in the 10 mg tofacitinib group, 54.9% vs. 51.8% of patients receiving ≤15 mg methotrexate per week vs. ≥15 mg per week achieved ACR20. No new safety risks were identified.

Study details: Findings are from pooled, post hoc exploratory analysis of 2 phase 3 trials, OPAL Broaden and OPAL Beyond, including 556 patients with active PsA randomly assigned to tofacitinib (5 mg or 10 mg twice daily) or placebo, with stable methotrexate.

Disclosures: This study was funded by Pfizer. Some of the authors reported ties with various sources, including Pfizer. C Wang and L Takiya declared being employees and shareholders of Pfizer.

Source: Kivitz AJ et al. Clin Rheumatol. 2021 Sep 12. doi: 10.1007/s10067-021-05894-2.

Key clinical point: Patients with psoriasis who experienced nail pitting, musculoskeletal symptoms, or inflammation or had high body mass index (BMI) were at a higher risk of developing psoriatic arthritis (PsA).

Major finding: Patients with psoriasis who had arthralgia (pooled risk ratio [pRR] 2.15; 95% CI 1.16-3.99) or imaging-detected musculoskeletal inflammation or structural damage (pRR 3.72; 95% CI 2.12-6.51) were at a significantly higher risk for PsA. Other predictors of PsA included nail pitting (pooled hazard ratio [HR] 2.14; 95% CI 1.32-3.46) and higher BMI (adjusted HR 1.17; 95% CI 1.04-1.31).

Study details: Findings are from a meta-analysis of 16 cohort studies and 10 case-control studies including patients with skin/nail psoriasis without a diagnosis of PsA.

Disclosures: This study was partially funded by Novartis Farma, Italy. The authors declared no conflict of interests.

Source: Zabotti A et al. Rheumatol Ther. 2021 Oct 10. doi: 10.1007/s40744-021-00378-w.

Key clinical point: Patients with psoriasis who experienced nail pitting, musculoskeletal symptoms, or inflammation or had high body mass index (BMI) were at a higher risk of developing psoriatic arthritis (PsA).

Major finding: Patients with psoriasis who had arthralgia (pooled risk ratio [pRR] 2.15; 95% CI 1.16-3.99) or imaging-detected musculoskeletal inflammation or structural damage (pRR 3.72; 95% CI 2.12-6.51) were at a significantly higher risk for PsA. Other predictors of PsA included nail pitting (pooled hazard ratio [HR] 2.14; 95% CI 1.32-3.46) and higher BMI (adjusted HR 1.17; 95% CI 1.04-1.31).

Study details: Findings are from a meta-analysis of 16 cohort studies and 10 case-control studies including patients with skin/nail psoriasis without a diagnosis of PsA.

Disclosures: This study was partially funded by Novartis Farma, Italy. The authors declared no conflict of interests.

Source: Zabotti A et al. Rheumatol Ther. 2021 Oct 10. doi: 10.1007/s40744-021-00378-w.

Key clinical point: Patients with psoriasis who experienced nail pitting, musculoskeletal symptoms, or inflammation or had high body mass index (BMI) were at a higher risk of developing psoriatic arthritis (PsA).

Major finding: Patients with psoriasis who had arthralgia (pooled risk ratio [pRR] 2.15; 95% CI 1.16-3.99) or imaging-detected musculoskeletal inflammation or structural damage (pRR 3.72; 95% CI 2.12-6.51) were at a significantly higher risk for PsA. Other predictors of PsA included nail pitting (pooled hazard ratio [HR] 2.14; 95% CI 1.32-3.46) and higher BMI (adjusted HR 1.17; 95% CI 1.04-1.31).

Study details: Findings are from a meta-analysis of 16 cohort studies and 10 case-control studies including patients with skin/nail psoriasis without a diagnosis of PsA.

Disclosures: This study was partially funded by Novartis Farma, Italy. The authors declared no conflict of interests.

Source: Zabotti A et al. Rheumatol Ther. 2021 Oct 10. doi: 10.1007/s40744-021-00378-w.

Key clinical point: Almost 80% of the effect of tofacitinib treatment on health-related quality of life (HRQoL) is primarily mediated by improvement in itch and Physician’s Global Assessment of psoriasis (PGA-PsO).

Major finding: Overall, 82.3% of the effect of tofacitinib on HRQoL as measured by the Dermatology Life Quality Index was contributed by improvement in itch score (P < .0001) and 17.7% was attributed to improvement in PGA-PsO score (P = 0.0006).

Study details: Findings are from a post hoc analysis of phase 3 trials OPAL Broaden and OPAL Beyond including 468 patients with active psoriatic arthritis (PsA), randomly assigned to tofacitinib (5 mg or 10 mg twice a day), adalimumab 40 mg (only in OPAL Broaden), or placebo.

Disclosures: This study was funded by Pfizer. The authors declared receiving grants or serving as consultants for several pharmaceutical companies, including Pfizer. Four authors declared being employees and stockholders of Pfizer.

Source: Taylor PC et al. J Clin Med. 2021 (Sep 9);10(18):4081. doi: 10.3390/jcm10184081.

Key clinical point: Almost 80% of the effect of tofacitinib treatment on health-related quality of life (HRQoL) is primarily mediated by improvement in itch and Physician’s Global Assessment of psoriasis (PGA-PsO).

Major finding: Overall, 82.3% of the effect of tofacitinib on HRQoL as measured by the Dermatology Life Quality Index was contributed by improvement in itch score (P < .0001) and 17.7% was attributed to improvement in PGA-PsO score (P = 0.0006).

Study details: Findings are from a post hoc analysis of phase 3 trials OPAL Broaden and OPAL Beyond including 468 patients with active psoriatic arthritis (PsA), randomly assigned to tofacitinib (5 mg or 10 mg twice a day), adalimumab 40 mg (only in OPAL Broaden), or placebo.

Disclosures: This study was funded by Pfizer. The authors declared receiving grants or serving as consultants for several pharmaceutical companies, including Pfizer. Four authors declared being employees and stockholders of Pfizer.

Source: Taylor PC et al. J Clin Med. 2021 (Sep 9);10(18):4081. doi: 10.3390/jcm10184081.

Key clinical point: Almost 80% of the effect of tofacitinib treatment on health-related quality of life (HRQoL) is primarily mediated by improvement in itch and Physician’s Global Assessment of psoriasis (PGA-PsO).

Major finding: Overall, 82.3% of the effect of tofacitinib on HRQoL as measured by the Dermatology Life Quality Index was contributed by improvement in itch score (P < .0001) and 17.7% was attributed to improvement in PGA-PsO score (P = 0.0006).

Study details: Findings are from a post hoc analysis of phase 3 trials OPAL Broaden and OPAL Beyond including 468 patients with active psoriatic arthritis (PsA), randomly assigned to tofacitinib (5 mg or 10 mg twice a day), adalimumab 40 mg (only in OPAL Broaden), or placebo.

Disclosures: This study was funded by Pfizer. The authors declared receiving grants or serving as consultants for several pharmaceutical companies, including Pfizer. Four authors declared being employees and stockholders of Pfizer.

Source: Taylor PC et al. J Clin Med. 2021 (Sep 9);10(18):4081. doi: 10.3390/jcm10184081.